Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Abstract

Clinical studies have revealed that genetic variations in metabotropic glutamate receptor 3 (mGlu 3 ) affect performance on cognitive tasks dependent upon the prefrontal cortex (PFC) and may be linked to psychiatric conditions such as schizophrenia, bipolar disorder, and addiction. We have performed a series of studies aimed at understanding how mGlu 3 influences PFC function and cognitive behaviors. In the present study, we found that activation of mGlu 3 can induce long-term depression in the mouse medial PFC (mPFC) in vitro. Furthermore, in vivo administration of a selective mGlu 3 negative allosteric modulator impaired learning in the mPFC-dependent fear extinction task. The results of these studies implicate mGlu 3 as a major regulator of PFC function and cognition. Additionally, potentiators of mGlu 3 may be useful in alleviating prefrontal impairments associated with several CNS disorders.etabotropic glutamate receptor 3 (mGlu 3 ) has become of increasing clinical interest due to its genetic association with psychiatric conditions. For example, several studies have identified single-nucleotide polymorphisms (SNPs) in GRM3, the human gene encoding mGlu 3 , that are associated with poor performance on cognitive tests that are dependent on function of the prefrontal cortex (PFC) and hippocampus (1, 2). Additionally, these SNPs have also been associated with variations in functional magnetic resonance imaging (fMRI) indexes of prefrontal cortical activity during working memory tasks (1, 3). Moreover, converging lines of evidence indicate that GRM3 represents a major locus associated with schizophrenia (1, 2, 4), bipolar disorder (5, 6), and substance abuse disorders (6-8). Because mGlu 3 is densely expressed in PFC (9), a brain region implicated as a site of pathology in these disorders (10-12), this genetic evidence has led to an increased interest in determining the role of mGlu 3 in regulating PFC function and behavior.Previous studies have revealed that pharmacological activation of group II mGlu receptors (mGlu 2 and mGlu 3 ) results in longterm depression (LTD) of excitatory transmission in layer V of the rat medial prefrontal cortex (mPFC) (13-16). Although it is not known whether induction of LTD in the mPFC is mediated by mGlu 2 or mGlu 3 , previous studies suggest that presynaptically localized mGlu 2 is typically responsible for inhibition of synaptic transmission by group II mGlu receptor agonists at other synapses (17-23). However, evidence suggests that induction of LTD in the mPFC is dependent upon activation of a postsynaptic group II mGlu receptor (15, 16), suggesting that this response is mechanistically distinct from presynaptic effects of group II mGlu receptor agonists on transmission at other synapses. Unfortunately, a lack of pharmacological agents that can selectively antagonize mGlu 3 or mGlu 2 has impaired progress in this area. To allow us to begin studies aimed at understanding the role of mGlu 3 in regulation of mPFC function, we developed a series of negative allosteric modulator...

Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model

“…Similarly, 100 μM CCh also failed to induce any form of mLTD in these PCP-treated mice (n = 5; 97.1 ± 6.3%). In contrast, a previously reported form of mGlu 2/3 agonist LY379268-mediated glutamatergic LTD (Walker et al, 2015) was unaffected in the PCP-treated mice (Supplementary Figure S5a and b). This indicated that the deficit in mLTD is specific to deficits in muscarinic plasticity.…”

“…One can also argue that this mLTD deficit is a general dysfunction in overall plasticity-related mechanisms in the PFC. However, we found that glutamatergic LTD mediated by the group II mGlu receptor mGlu3 (Walker et al, 2015) is intact in the PFC after PCP treatment, indicating PFC synapses can still undergo plastic changes in these mice. It is possible that mLTD and group II mGlu receptor-mediated LTD can reflect plasticity in distinct synapses in the PFC, thus serving distinct functions, and repeated PCP treatment leads to selective mLTD deficits and deficits in functions only related to this form of muscarinic plasticity.…”

Group II mGluRs modulate baseline and arthritis pain-related synaptic transmission in the rat medial prefrontal cortex

“…Recent evidence suggests that LTD in the mPFC is mediated through postsynaptic mGluR3 but not mGluR2. An mGluR3 negative allosteric modulator blocked LTD induced by LY379268 but not acute synaptic inhibition by LY379268 [43]. We did not measure LTD but our data on acute inhibitory effects of LY379268 would be consistent with the involvement of mGluR2 rather than mGluR3.…”

“…Group II mGluR antagonists had beneficial effects in an Alzheimer's Disease mouse model, improving cognitive functions and anxiety [22]. However, mGluR3 negative allosteric modulators impaired extinction of conditioned fear [43]. These findings suggest that group II mGluRs play complex roles in cognitive-affective functions and disorders and could also be useful targets to normalize deficits associated with pain such as medial prefrontal cortical dysfunction.…”

“…Synaptic effects of group II mGluRs in the prefrontal cortex include a decrease of serotonin-induced or electrically-evoked excitatory synaptic responses of layer V pyramidal cells by group II agonists and enhancement by group II antagonists [27]. A recent study found that presynaptic mGluR2 mediates acute synaptic inhibition of excitatory transmission in the mPFC whereas long long-term depression depends on postsynaptic mGluR3 [43]. In this study, we examined the effects of a selective group II mGluR agonist (LY379268) and antagonist (LY341495) on excitatory and inhibitory synaptic transmission and output of infralimbic mPFC pyramidal cells in brain slices from normal rats and from rats with arthritis.…”